1. Field of the Invention
This invention relates to the field of drug delivery. In particular, the present invention relates to methods, devices and systems adapted to sub-chronic implantation (less than or equal to 12 months and typically less or equal to about 6 months) in the patient""s body to deliver a drug or other pharmaceutical agent at a sustained rate.
2. Description of the Related Art
Since the beginning of modern medicine, drugs have been administered orally. Patients have taken pills as recommended by their physician. The pills must pass through the digestive system and then the liver before they reach their intended delivery site (e.g., the vascular system). The actions of the digestive tract and the liver often reduce the efficacy of medication; furthermore, medications delivered systemically sometimes cause undesirable side effects. Over the course of the past few decades, drug delivery technology and administration has evolved from oral delivery to site-specific delivery. In addition to the oral route of administration, drugs are also routinely administered via the vascular system (intravenous or IV). Intravenous drug delivery has the advantage of bypassing the acidic and enzymatic action of the digestive system. Unfortunately, IV administration requires the use of a percutaneous catheter or needle to deliver the drug to the vein. The percutaneous site requires extra cleanliness and maintenance to minimize the risk of infection. Infection is such a significant risk that IV administration is often limited to a number of weeks, at most. In addition, the patient must wear an external pump connected to the percutaneous catheter.
The next step in the evolution of drug delivery was the implanted pump. The implanted pump is a device that is completely implanted under the skin of a patient, thereby negating the need for a percutaneous catheter. These implanted pumps provide the patient with a drug at a constant or a programmed delivery rate. Constant rate or programmable rate pumps are based on either phase-change or peristaltic technology. When a constant, unchanging delivery rate is required, a constant-rate pump is well suited for long-term implanted drug delivery. If changes to the infusion rate are expected, a programmable pump may be used in place of the constant rate pump. Fully implanted constant rate and programmable rate infusion pumps have been sold in the United States for human use since the late 1970s and early 1980s, respectively. Two problems associated with such 1970s and 1980s vintage constant rate and programmable rate infusion pumps relate to their size and their cost. Current implantable constant rate and programmable pumps are about the size and shape of hockey pucks, and they typically are sold to the hospital for $5,000-$9,000. The current implantable pumps must be implanted in the Operating Room under general anesthesia, which further increases costs, as well as the risk, and discomfort to the patient. The size and cost of such pumps has proven to be a substantial barrier to their use, and they are rarely used to deliver medication. An added drawback of phase-change and peristaltic pumps is that they must be refilled with drug every 3-8 weeks. Refills constitute an added burden to the caregiver, and add further costs to an already overburdened healthcare system. The burden associated with such refills, therefore, further limits the use of phase-change and peristaltic pumps.
In the 1970s, a new approach toward implanted pump design was commercialized for animal use only. The driving force of the pumps based upon this new approach utilized the principle of osmosis. Osmotic pumps may be much smaller than other constant rate or programmable pumps, because their infusion rate can be very low. An example of such a pump is described listed in U.S. Pat. No. 5,728,396. This patent discloses an implantable osmotic pump that achieves a sustained delivery of leuprolide. The pump includes an impermeable reservoir that is divided into a water-swellable agent chamber and a drug chamber. Fluid from the body is imbibed through a semi permeable plug into the water-swellable agent chamber and the drug is released through a diffusion outlet at a substantially constant rate.
A limitation of the osmotic pump disclosed in the above-identified patent, however, is that its infusion rate cannot be adjusted once it is implanted. This is acceptable for medications that do not need rate adjustment, but often physicians desire to adjust the infusion rate based on the clinical status of the patient. One example of when a physician would want to increase the infusion rate is in the field of pain management. Implanted pumps can be used to deliver medication to treat pain lasting over an extended period of time. Pain, however, often increases with time, and sometimes patients become tolerant to pain medications; therefore, more medication is needed to effectively treat the pain. The system disclosed in the above-identified patent does not allow a rate increase after implantation, so the physician must either replace the current implant or implant an additional pump to replace or supplement the system. However, the prospect of yet another surgical procedure may cause many patients to forego the potential benefits of the larger dose and may also cause their physicians to advise against the initial procedure altogether. For such patients for whom the implantable pump no longer delivers an adequate dosage of medication, the physician may opt to supplement the dosage delivered by the implantable device by other means, such as by intravenous delivery, in which case the same side effects discussed above may again occur.
Pain management medications are only one example of medications that need to be increased in dosage over time. Other applications may include but are not limited to hypertensive medications, other cardiovascular medications, and medications to treat disorders of the brain and endocrine system.
An object of the present invention, therefore, is to provide methods and implantable devices and systems for long-term delivery of a pharmaceutical agent at selectable rates. It is another object of the present invention to provide implantable devices and systems for long term delivery of a drug that are small in size and that may be readily implanted in a physician""s procedure room or a radiology suite.
In accordance with the above-described objects and those that will be mentioned and will become apparent below, an implantable osmotic pump for delivering a pharmaceutical agent to a patient comprises a pump housing; a moveable partition disposed within the housing, the partition dividing the housing into an osmotic driving compartment having an open end and a pharmaceutical agent compartment having a delivery orifice; a first semi permeable membrane disposed in the open end of the osmotic driving compartment, the first semi permeable membrane being exposed to the patient; a second semi permeable membrane disposed in the open end of the osmotic driving compartment, and a first impermeable barrier disposed over the second semi permeable membrane, the second semi permeable membrane being sealed from the patient until the first barrier is breached, wherein breaching the first barrier increases the surface area of semi permeable membrane exposed to the patient and increases a delivery rate of the pharmaceutical agent through the delivery orifice.
According to further embodiments, the first impermeable barrier may include titanium and/or stainless steel. A saturated solution including NaCl may be present between the first impermeable barrier and the second semi permeable membrane. The first and second semi permeable membranes may the same composition and/or may have the same thickness. Alternatively, the first and second semi permeable membranes may have mutually different compositions and/or mutually different thickness. The pump may further include a third semi permeable member, and a second impermeable barrier may be nested within the first impermeable barrier. The second impermeable barrier may be disposed over the third semi permeable membrane and may seal the third semi permeable membrane from the patient until the second impermeable barrier is breached. Breaching the second barrier increases the surface area of semi permeable membrane exposed to the patient and increases the delivery rate of the pharmaceutical agent through the delivery orifice.
A saturated solution including NaCI may be present between the second barrier and the third semi permeable membrane. The pharmaceutical agent compartment may contain sufentanil, for example, and may also contain other medications. The sufentanil may be at a concentration selected between about 200 xcexcg/mL and about 15,000 xcexcg/mL. The daily delivery rate of the pharmaceutical agent through the delivery orifice may be selected from about 0.5 micrograms per day to about 25 micrograms per day when the pump is configured to be implanted intraventricularly; about 0.5 micrograms per day to about 50 micrograms per day when the pump is configured to be implanted intrathecally; about 5 micrograms per day to about 300 micrograms per day when the pump is configured to be implanted epidurally; about 10 micrograms per day to about 300 micrograms per day when the pump is configured to be implanted subcutaneously.
The first and second semi permeable membranes may include cellulose acetate. The first semi permeable membrane may be shaped as a torus and may be disposed adjacent the outer periphery of the first impermeable barrier. The second semi permeable membrane may be disposed in the center opening of the torus.
A catheter may be coupled to the delivery orifice and the catheter may have an inner diameter of between about 0.001 inches and about 0.010 inches. The catheter may include a guidewire lumen and a pharmaceutical agent infusion lumen. The pharmaceutical agent infusion lumen may have an inner diameter selected between about 0.001 inches to about 0.010 inches. The catheter and the pump may be dimensioned to infuse a volume of pharmaceutical agent of between about 1 xcexcL/day and about 10 xcexcL/day over a treatment period. The catheter and the pump may be dimensioned to infuse a dose of pharmaceutical agent of between about 0.5 xcexcg/day and about 300 xcexcg/day over a treatment period.
At least a portion of the catheter may be radiopaque. The guidewire lumen may include a valve to prevent back flow of fluid into the guidewire lumen.
The present invention is also a method for achieving an analgesic effect in a patient. The method comprises the step of administering a therapeutically effective dose of a sufentanil-containing analgesic to the patient using a device that is fully implanted in the patient. The dose may be administered intravascularly, subcutaneously, epidurally, intrathecally or intraventricularly. A step of selectively increasing the dose in a stepwise manner over a treatment period without removing the device from the patient may also be carried out. The dose may be administered using an implanted osmotic pump that includes a first semi permeable membrane exposed to the patient and a second semi permeable membrane initially not exposed to the patient and wherein the increasing step may include a step of exposing the second semi permeable membrane to the patient. The second semi permeable membrane exposing step may include a step of breaching an impermeable barrier sealing the second semi permeable membrane from the patient. The breaching step may include a step of puncturing the impermeable barrier using a lancet while the pump remains implanted in the patient. The therapeutically effective dose may be selected within the range of about 0.5 xcexcg/day to about 300 xcexcg/day.
According to another embodiment, the present invention may also be viewed as a method for achieving an analgesic effect in a patient, the method comprising intraspinal administration of a therapeutically-effective dose of an analgesic to the patient by an osmotic pump and catheter integrated combination, the pump including a first semi permeable membrane across which an osmotic pressure gradient develops when the pump is implanted in the patient.
The method may also include the step of selectively increasing a surface area of semi permeable membrane exposed to the patient in a stepwise manner. The analgesic may include sufentanil and/or other medication(s). A second semi permeable membrane may be provided, and the surface area of semi permeable membrane exposed to the patient may be increased by breaching an impermeable barrier initially sealing the second semi permeable membrane from the patient. For example, the impermeable barrier may be breached by puncturing the impermeable barrier. The dose may be increased in a stepwise manner by sequentially breaching one of a plurality of nested impermeable barriers disposed over a corresponding plurality of the semi permeable membranes, each sequential breach exposing additional surface area of semi permeable membrane to the patient. Each of the plurality of nested barriers may be configured to be breached by a lancet, an outer diameter of the lancet determining which of the plurality of nested barriers is breached. The analgesic may be administered intravascularly, subcutaneously, epidurally or intrathecally. The second semi permeable membrane may have the same or a different composition as the first semi permeable membrane. Similarly, the second semi permeable membrane may have the same or a different thickness as the first semi permeable membrane.
The present invention is also an integrated implantable pump and catheter system for delivering a dose of sufentanil to a patient over a treatment period, comprising a pump housing; a moveable partition disposed within the housing, the partition dividing the housing into an driving engine compartment and a pharmaceutical agent compartment having a delivery orifice; a catheter coupled to the delivery orifice, and a preloaded amount of sufentanil in the pharmaceutical agent compartment.
The pump and the catheter may be dimensioned to deliver sufentanil at an infusion rate of about 0.5 xcexcg/day to about 300 xcexcg/day over a treatment period. The system further may further include a mechanical infusion rate selection structure configured to allow the infusion rate of the pump to be increased while the system is implanted in the patient. The infusion rate selection feature may include a plurality of semi permeable membranes across each of which osmotic pressure develops when selectively and sequentially exposed to the patient. Each of the plurality of semi permeable membranes may have the same or a different thickness, composition and surface area, the selected thickness, composition and surface area contributing to a rate at which the sufentanil is infused into the patient.
The present invention also encompasses a kit comprising an osmotic pump; sufentanil preloaded in the osmotic pump, and a delivery catheter configured to be coupled to the osmotic pump. The osmotic pump may include a mechanical infusion rate selection structure. The kit may further include a lancet configured to act upon the infusion rate selection structure to increase an infusion rate of the sufentanil through the delivery catheter. The pump may be configured to deliver sufentanil at an infusion rate of a bout 0.5 xcexcg/day to about 300 xcexcg/day over a treatment period. The catheter may include a guidewire lumen and a sufentanil delivery lumen. The kit may further include a guidewire. The kit may also include a guidewire, a needle and a splittable introducer. According to still further embodiments, the needle may be a hypodermic needle or a non-coring needle, for example.
The present invention is also a kit comprising an osmotic pump that includes a mechanical infusion rate selection structure; an amount of pharmaceutical agent preloaded into the pump, and a delivery catheter. The pharmaceutical agent may include sufentanil and/or other medication(s). The infusion rate selection structure may be configured to allow the infusion rate to be increased while the pump is implanted into a patient. The infusion rate selection structure may include a plurality of semi permeable membranes, each of which being selectably exposable to the patient to increase a dose of pharmaceutical agent delivered to the patient. Each of the plurality of semi permeable membranes may have an individually selected thickness, composition and/or surface area.
According to a still further embodiment thereof, the present invention is a method of delivering a pharmaceutical agent to a patient, comprising the steps of implanting an osmotic pump within the patient, the osmotic pump including the pharmaceutical agent and a plurality of semi permeable membranes across which osmotic pressure develops when exposed to the patient, and controlling a surface area of semi permeable membrane exposed to the patient to control an infusion rate of the pharmaceutical agent analgesic to the patient. A step of controlling the thickness and/or a composition of each of the plurality of semi permeable membranes may also be carried out.